Method for producing optically active carboxylic acid

ABSTRACT

A method for producing a desired optically active carboxylic acid with a high optical purity, wherein a complex catalyst used can be recovered and reused as an aqueous solution. The method contains the step of subjecting an &amp;agr;,&amp;bgr; -unsaturated carboxylic acid in water or a mixed solvent of water and a water-insoluble organic solvent in the presence of a sulfonated BINAP—Ru complex represented by the formula [3]: [RuX(arene){(SO?3#191M)?2#191-BINAP}]X [3]wherein X represents a chlorine atom, a bromine atom or an iodine atom, arene represents a benzene or an alkyl-substituted benzene, M represents an alkaline metal atom, and BINAP represents 2,2′-bis(diphenylphosphine)-1,1′-binaphthyl to an asymmetric hydrogenation. The sulfonated BINAP—Ru complex can be recycled.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method for producing an opticallyactive carboxylic acid useful as a pharmaceutical intermediate, a liquidcrystal material, perfumes, etc.

2. Description of the Related Art

Generally, most of pharmaceutical intermediates are solid and it isdifficult to separate a pharmaceutical intermediate from a catalyst bydistillation. Separation of catalysts and products is one of unavoidableproblems. Particularly, catalysts for use in homogeneous catalyticreactions are easily dissolved in organic phases, so that complicatedprocedures such as distillation and recrystallization are required toseparate such catalysts and products. One solution of the problem is amethod in which a reaction is carried out in a water-containing solventusing a water-soluble catalyst. In this method, the catalyst can beeasily separated only by extraction because the product is dissolved inthe organic phase and the catalyst is dissolved in the water phase.Water-soluble phosphine ligands have attracted attention as thewater-soluble catalyst, and many reports have been made thereon.

Asymmetric hydrogenation of ketones and imines using a sulfonated BINAPare described in JP-A-5-170780. However, asymmetric hydrogenation ofolefins are not described in the patent document, and reuse of thecatalyst dissolved in water, which is used in the reaction once, is alsonot described.

An example of synthesizing anti-inflammatory analgesic drug naproxen hasbeen reported in J. Catal., Vol. 148, Page 1, 1994. A ligand used in thesynthesis is such that BINAP(2,2′-bis(diphenylphosphine)-1,1′-binaphthyl) is sulfonated to havesulfone groups at all the meta positions of 4 phenyl groups. The ligandis converted to a ruthenium complex and used for hydrogenatingdehydronaproxen. Though the enantiomer excess of naproxen produced bythe asymmetric hydrogenation in methanol is 96.1% ee, the enantiomerexcess is considerably reduced to 77.6% ee in the case of the asymmetrichydrogenation in water/methanol.

Asymmetric hydrogenation of dehydronaproxen in water/ethyl acetate andrecycle of the water phase are also described in J. Catal., Vol. 148,Page 1, 1994. However, the enantiomer excess of naproxen obtained by theasymmetric hydrogenation is 81.1% ee, and the enantiomer excess isinsufficiently 82.7% ee in the case of recycling the water phase.Further, it takes 1.5 days to complete the asymmetric hydrogenation,whereby the synthesis method disadvantageously needs improvement ofworkability.

An example of asymmetric hydrogenation of tiglic acid is described in J.Mol. Cat., Vol. 159, Page 37, 2000. A ruthenium complex used in theasymmetric hydrogenation contains a ligand obtained by aminating carbonatoms at 5,5′-positions of BINAP and by introducing polyethylene glycol,etc. to make the BINAP water-soluble. The asymmetric hydrogenation iscarried out in a two-phase system of ethyl acetate/water solvent, and asa result, the enantiomer excess of the product is insufficiently 83% ee.Experiments of recycling the ruthenium complex catalyst are notdescribed in the reference.

As described above, though many reports have been made on asymmetrichydrogenation methods using water-soluble phosphine ligands in two-phasesystems of water and organic phases, most of the methods aredisadvantageous in enantiomer excess and catalytic activity to beimpractical. Further, most of the methods are unsatisfactory in view ofseparation of products and catalysts, reuse of catalysts, etc. dependingon intended reactions and substrates. The ligands and the transitionmetals contained in the optically active complex catalysts are extremelyexpensive, whereby it has been desired to develop a synthesis methodcapable of recycling the catalyst to most efficiently reduce productioncosts.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a method capable ofproducing a desired optically active carboxylic acid with a high opticalpurity, wherein a complex catalyst used can be recovered as an aqueoussolution and the recovered complex catalyst solution can be recycled, inview of the above-described situation.

A first method of the present invention for producing an opticallyactive carboxylic acid represented by the formula [2]:

wherein R¹, R² and R³ independently represent a hydrogen atom, an alkylgroup, an alkenyl group or an aryl group, the groups may have asubstituent, R¹, R² and R³ is not a hydrogen atom simultaneously, R³ isa group other than a hydrogen atom when one of R¹ and R² is a hydrogenatom, R³ is a group other than a hydrogen atom and a methyl group whenboth of R¹ and R² are hydrogen atoms, and R¹ and R² are different groupsother than a hydrogen atom when R³ is a hydrogen atom, and at least oneof the two carbon atoms marked with * represents an asymmetric carbonatom, comprising the step of subjecting an α,β-unsaturated carboxylicacid represented by the formula [1]:

wherein R¹ to R³ have the same meanings as those in the formula [2], inthe presence of a sulfonated BINAP—Ru complex represented by the formula[3]:[RuX(arene){(SO₃M)₂-BINAP}]X  [3]wherein (SO₃M)₂-BINAP represents a tertiary phosphine represented by thegeneral formula [4]:

M represents an alkaline metal atom, X represents a chlorine atom, abromine atom or an iodine atom, and arene represents a benzene or analkyl-substituted benzene, in an aqueous solvent, to an asymmetrichydrogenation.

A second method of the invention for producing an optically activecarboxylic acid represented by the formula [2]:

wherein R¹, R² and R³ independently represent a hydrogen atom, an alkylgroup, an alkenyl group or an aryl group, the groups may have asubstituent, R¹, R² and R³ is not a hydrogen atom simultaneously, R³ isa group other than a hydrogen atom when one of R¹ and R² is a hydrogenatom, R³ is a group other than a hydrogen atom and a methyl group whenboth of R¹ and R² are hydrogen atoms, and R¹ and R² are different groupsother than a hydrogen atom when R³ is a hydrogen atom, and at least oneof the two carbon atoms marked with * represents an asymmetric carbonatom, comprising the step of subjecting an α,β-unsaturated carboxylicacid represented by the formula [1]:

wherein R¹ to R³ have the same meanings as those described above, in thepresence of a recovered sulfonated BINAP—Ru complex used in the firstmethod in water or a mixed solvent of water and a water-insolubleorganic solvent to an asymmetric hydrogenation.

Thus, as a result of intense research in view of the above object, theinventors have found that an optically active carboxylic acid with ahigh optical purity can be obtained by asymmetric hydrogenation of theα,β-unsaturated carboxylic acid using the sulfonated BINAP—Ru complexrepresented by the formula [3] in an aqueous solvent such as water orthe mixed solvent of water and the water-insoluble organic solvent andthat the complex catalyst can be recycled while maintaining highcatalytic activity. The invention has been achieved by the findings.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the formulae [1] and [2], the alkyl group represented by R¹, R² or R³may be a linear, branched or cyclic alkyl group having a carbon numberof 1 to 20, preferably 1 to 15, more preferably 1 to 10. Specificexamples of the alkyl groups include a methyl group, an ethyl group, an-propyl group, a 2-propyl group, a n-butyl group, a 2-butyl group, anisobutyl group, a tert-butyl group, a n-pentyl group, a 2-pentyl group,a 2-methylbutyl group, a 3-methylbutyl group, a 2,2-dimethylpropylgroup, a n-hexyl group, a 2-hexyl group, a 3-hexyl group, a2-methylpentane-2-yl group, a 3-methylpentane-3-yl group, a2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a2-methylpentane-3-yl group, a heptyl group, an octyl group, a2-ethylhexyl group, a nonyl group, a decyl group, a cyclopropyl group, acyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc.

The alkenyl group represented by R¹, R² or R³ may be such that 1 or moredouble bond is introduced to the above alkyl groups having 2 or morecarbon atoms. Specific examples of the alkenyl groups include an ethenylgroup, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, a1-butenyl group, a 2-butenyl group, a 1,3-butadienyl group, a 2-pentenylgroup, a 2-hexenyl group, a heptenyl group, an octenyl group, a nonenylgroup, a decenyl group, a cyclopropenyl group, a cyclopentenyl group, acyclohexenyl group, etc.

The aryl group represented by R¹, R² or R³ may be an aryl group having 6to 14 carbon atoms. Specific examples of the aryl groups include aphenyl group, a naphthyl group, an anthryl group, a biphenyl group, etc.

The substituent bonding to the alkyl, alkenyl or aryl group, i.e.substituent of a substituted alkyl group, a substituted alkenyl group ora substituted aryl group, may be any group that has no adverse affect onthe asymmetric hydrogenation of the invention, and examples thereofinclude alkyl groups, alkoxy groups, aryl groups, halogen atoms, etc.

The meanings and specific examples of the alkyl groups and the arylgroups as the substituent may be the same as those described above.

The alkoxy group may be a linear, branched or cyclic group having 1 to20, preferably 1 to 10, more preferably 1 to 6 carbon atoms. Specificexamples of the alkoxy groups include a methoxy group, an ethoxy group,a n-propoxy group, a 2-propoxy group, a n-butoxy group, a 2-butoxygroup, an isobutoxy group, a tert-butoxy group, a n-pentyloxy group, a2-methylbutoxy group, a 3-methylbutoxy group, a 2,2-dimethylpropyloxygroup, a n-hexyloxy group, a 2-methylpentyloxy group, a3-methylpentyloxy group, a 4-methylpentyloxy group, a 5-methylpentyloxygroup, a cyclohexyloxy group, etc.

Examples of the halogen atoms include a fluorine atom, a chlorine atom,a bromine atom, an iodine atom, etc.

In the formulae [1] and [2], R¹, R² and R³ represent the above atom orgroup respectively, and it should be noted that R¹, R² and R³ is not ahydrogen atom simultaneously based on the definition that at least oneof the two carbon atoms marked with * in the formula [2] represents anasymmetric carbon atom. Further, R³ is a group other than a hydrogenatom when one of R¹ and R² is a hydrogen atom, R³ is a group other thana hydrogen atom and a methyl group when both of R¹ and R² are hydrogenatoms, and R¹ and R² are different groups other than a hydrogen atomwhen R³ is a hydrogen atom.

This is because, in the formula [2], the carbon atom bonding to R¹ andR² is not an asymmetric carbon atom in the case where R¹ and/or R² is ahydrogen atom, and the carbon atom bonding to R³ is not an asymmetriccarbon atom in the case where R³ is a hydrogen atom or in the case whereboth of R¹ and R² are hydrogen atoms and R³ is a methyl group.

In the formula [3], arene represents a benzene or an alkyl-substitutedbenzene. Examples of preferred alkyl-substituted benzenes includep-cymene, hexamethylbenzene, 1,3,5-trimethylbenzene, etc.

In the formulae [3] and [4], the alkaline metal atom represented by Mmay be a sodium atom, a potassium atom, etc.

Specific examples of the α,β-unsaturated carboxylic acids represented bythe formula [1], used as a starting material in the methods of theinvention, include 2-methylbutenoic acid, 2-methyl-2-pentenoic acid,2-methyl-2-hexenoic acid, 2-ethyl-2-hexenoic acid, 2-methyl-2-heptenoicacid, 2-methyl-2-octenoic acid, etc.

Specific examples of the sulfonated BINAP—Ru complexes represented bythe formula [3] used in the methods of the invention include[RuI(p-cymene) {(SO₃Na)₂—BINAP}]I, [RuBr(p-cymene) {(SO₃Na)₂—BINAP}]Br,[RuCl(p-cymene) {(SO₃Na)₂—BINAP}]Cl, [RuI(C₆H₆){(SO₃Na)₂—BINAP}]I,[RuBr(C₆H₆) {(SO₃Na)₂—BINAP}]Br, [RuCl(C₆H₆){(SO₃Na)₂—BINAP}]Cl, etc.

The sulfonated BINAP—Ru complexes can be easily produced by the methodsdescribed in JP-A-5-170780.

Specific examples of the optically active carboxylic acids representedby the formula [2], obtainable by the methods of the invention, include(2R)-methylbutanoic acid, (2R)-methylpentanoic acid, (2R)-methylhexanoicacid, (2R)-ethylhexanoic acid, (2R)-methylheptanoic acid,(2R)-methyloctanoic acid, (2S)-methylbutanoic acid, (2S)-methylpentanoicacid, (2S)-methylhexanoic acid, (2S)-ethylhexanoic acid,(2S)-methylheptanoic acid, (2S)-methyloctanoic acid, etc.

In the methods of the invention, the mole ratio of the sulfonatedBINAP—Ru complex represented by the formula [3] to the α,β-unsaturatedcarboxylic acid is appropriately selected generally from the range of1×10⁻² to 3×10⁻⁴ mol/mol, preferably from the range of 1×10⁻³ to 2×10⁻⁴mol/mol.

In the methods of the invention, the asymmetric hydrogenation is carriedout in an aqueous solvent. The aqueous solvent is water or the two-phasemixed solvent of water and the water-insoluble organic solvent.

Specific examples of the water-insoluble organic solvents used in themethods of the invention include aliphatic hydrocarbons such as pentane,hexane heptane, octane, decane, and cyclohexane; halogenatedhydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform,carbon tetrachloride, and 1,2-dichlorobenzene; ethers such as diethylether, diisopropyl ether, dimethoxyethane, ethylene glycol diethylether, tert-butyl methyl ether, and cyclopentyl methyl ether; esterssuch as methyl acetate, ethyl acetate, n-butyl acetate, and methylpropionate; etc. These solvents may be used alone or in appropriatecombination of two or more solvents thereof.

The amount of the water-insoluble organic solvent is appropriatelyselected generally from the range of 1 to 10 parts by weight, preferablyfrom the range of 2 to 5 parts by weight, per 1 part by weight of theα,β-unsaturated carboxylic acid.

Water used in the methods of the invention may be distilled water,purified water, ion-exchange water, etc. Water is preferably distilledand degassed.

The amount of water is appropriately selected generally from the rangeof 1 to 25 parts by weight, preferably from the range of 1 to 15 partsby weight, per 1 part by weight of the α,β-unsaturated carboxylic acid.The amount of water remarkably affects the asymmetric hydrogenation ratedepending on the carbon number of the α,β-unsaturated carboxylic acid.The amount of water may be 1 to 2 parts by weight in the case of tiglicacid having 5 carbon atoms, and the amount is 10 parts or more by weightin the case of 2-ethylhexenoic acid having 8 carbon atoms.

In the asymmetric hydrogenation of the invention, the hydrogen pressureis desirably 0.1 MPa or more, and appropriately selected generally fromthe range of 0.5 to 10 MPa, preferably from the range of 1 to 5 MPa,from the viewpoint of economical efficiency, etc.

The reaction temperature in the methods of the invention isappropriately selected generally from the range of 30 to 100° C.,preferably from the range of 40 to 90° C.

The reaction time depends on the conditions such as the reactiontemperature, the amount of the sulfonated BINAP—Ru complex, the amountof water, and the hydrogen pressure. The reaction time is appropriatelyselected generally from the range of 1 to 20 hours, preferably from therange of 3 to 10 hours.

In the methods of the invention, an aqueous solution of the sulfonatedBINAP—Ru complex used in the asymmetric hydrogenation can be recoveredand reused.

Thus, the sulfonated BINAP—Ru complex can be recycled (reused) in themethods of the invention.

The sulfonated BINAP—Ru complex or the aqueous solution thereof may berecovered by a common operation from the reaction solution (reactionsystem).

Specifically, the aqueous solution of the sulfonated BINAP—Ru complexmay be recovered by separating the water phase from the two-phasereaction solution after the asymmetric hydrogenation.

Further, the sulfonated BINAP—Ru complex can be easily recovered fromthe separated water phase by concentration, etc.

The recovered aqueous solution of the sulfonated BINAP—Ru complex (thewater phase separated after the asymmetric hydrogenation) may bedirectly reused (recycled) without aftertreatments and purifications forthe asymmetric hydrogenation of the α,β-unsaturated carboxylic acid.

The isolated or recovered sulfonated BINAP—Ru complex may be reused forthe asymmetric hydrogenation of the α,β-unsaturated carboxylic acid orfor other asymmetric hydrogenation after aftertreatment, purification,etc.

In the case where the recovered sulfonated BINAP—Ru complex, which maybe the water phase containing the sulfonated BINAP—Ru complex recoveredfrom the reaction solution (reaction system) or the sulfonated BINAP—Rucomplex isolated from the water phase, is recycled for the asymmetrichydrogenation of the α,β-unsaturated carboxylic acid to produce theoptically active carboxylic acid, the amount of the sulfonated BINAP—Rucomplex may be appropriately controlled if necessary by adding furthersulfonated BINAP—Ru complex, etc.

Thus-obtained optically active carboxylic acid is useful aspharmaceutical intermediates, liquid crystal materials, etc.

EXAMPLES

The present invention will be described in more detail below withreference to Examples without intention of restricting the scope of theinvention.

In Examples, physical properties are measured by the followingapparatuses.

1) Chemical Purity

Gas chromatography (GLC): TC-WAX column.

2) Optical Purity

Carboxylic acids were converted to L-(−)-1-phenylethylamides to measurethe optical purities.

Gas chromatography (GLC): Chiraldex G-PN column.

3) Optical Rotation

JASCO DIP-360 polarimeter.

4) Mass Spectrum

Shimadzu GC-MS-QP2010.

GLC column: TC-WAX.

Example 1 Synthesis of (2R)-methylbutanoic acid

10 g (0.1 mol) of tiglic acid (available from Tokyo Kasei Kogyo Co.,Ltd.) and 8.7 mg (6.6×10⁻³ mmol) of [RuI(p-cymene){(R)—(SO₃Na)₂BINAP}]Iwere put in a 200 mL autoclave, and the atmosphere in the autoclave wasreplaced with nitrogen. 20 mL of methylene chloride, which was degassedand distilled while blocking air flow by nitrogen, and 10 mL of degasseddistilled water were added to the mixture, and tiglic acid was reactedat 80° C. for 4 hours under the hydrogen pressure of 2.5 MPa. Thetemperature of the autoclave was lowered to the room temperature,hydrogen was discharged, and nitrogen was flowed in the autoclave forapproximately 30 minutes to remove the remaining hydrogen. The reactionsolution was taken out of the autoclave and left for approximately 30minutes. The reaction solution was separated into two layers, the oilphase of the lower layer and the water phase of the upper layer. Themethylene chloride solution in the lower layer was isolated and thewater phase was extracted with methylene chloride once. The methylenechloride solutions were mixed, dried over anhydrous magnesium sulfate,and concentrated to recover the solvent, whereby 9.8 g of crude(2R)-methylbutanoic acid was obtained. The crude (2R)-methylbutanoicacid was distilled to obtain 9.3 g of purified (2R)-methylbutanoic acid:boiling point 85° C./11 mmHg; GC purity 99.7%; optical purity 94.8% ee;optical rotation [α]_(D) ²⁰-19.5 (c 1.04, MeOH); mass spectrum (20 eV,m/e) 29, 41, 55, 56, 57, 73, 74, 87, and 103 (M⁺+1).

Example 2 Syntheses of (2R)-methylbutanoic acid Via Process of RecyclingWater Phase

10 g (0.1 mol) of tiglic acid (available from Tokyo Kasei Kogyo Co.,Ltd.) and 11.3 mg (1×10⁻² mmol) of [RuCl(p-cymene){(R)—(SO₃Na)₂BINAP}]Clwere put in a 200 mL autoclave, and the atmosphere in the autoclave wasreplaced with nitrogen. 40 mL of degassed distilled diisopropyl etherand 20 mL of degassed distilled water were added to the mixture, andtiglic acid was reacted at 80° C. for 3 hours under the hydrogenpressure of 2.5 MPa. The temperature of the autoclave was lowered to theroom temperature, hydrogen was discharged, and nitrogen was flowed inthe autoclave for approximately 30 minutes to remove the remaininghydrogen. Then, the reaction solution was ejected from a sampling holeof the autoclave into a 100 mL glass syringe having a needle with theinside diameter of 1.5 mm under nitrogen flow utilizing the nitrogenpressure, and left for approximately 30 minutes. The reaction solutionwas separated into two layers, the organic phase of the upper layer andthe water phase of the lower layer.

The water phase was isolated and returned into the autoclave, and sealedunder nitrogen to be reused in the next reaction. On the other hand, theoil phase was isolated, dried over anhydrous magnesium sulfate, andconcentrated to recover the solvent, whereby 9.61 g of a residue wasobtained. The residue was distilled to obtain 9.3 g of purified(2R)-methylbutanoic acid: boiling point 83° C./10 mmHg; GC purity 99.6%;optical purity 92.5% ee; optical rotation [α]_(D) ²⁰-19.2 (c 1.07,MeOH).

Then, a solution of 10 g (0.1 mol) of tiglic acid and 40 mL of degasseddistilled diisopropyl ether was added into the autoclave containing thewater phase used in the above reaction while blocking the air. Thetiglic acid was reacted for 3 hours under the same conditions as theabove reaction, and subjected to the aftertreatments in the same manneras above to obtain 10.2 g of crude (2R)-methylbutanoic acid: GC purity99.47%; enantiomer excess 92.5% ee.

The asymmetric hydrogenation of tiglic acid was repeated 4 times suchthat the water phase was isolated under nitrogen after the reaction andrecycled in the same manner as above.

It took 4 hours and 5 hours to complete the third and fourth reactionsrecycling the water phase, respectively. It was considered that thereaction rate was lowered because the water phase containing thecatalyst was mixed in the organic phase and removed with the organicphase.

The results of the reactions recycling the water phase are shown inTable 1. TABLE 1 Number of Yield of crude recycling Reaction Conver-Selec- 2-methyl- Optical water time sion tivity butanoic acid purityphase (h) (%) (%) (g) (% ee) 0 3 99.82 100 9.61 92.5 1 3 99.47 100 10.1992.5 2 3 98.34 100 10.67 92.3 3 4 97.26 100 10.48 92.3 4 5 96.7 100 9.6892.2

Example 3 Synthesis of (2R)-methylpentanoic acid

11.4 g (0.1 mol) of trans-2-methyl-2-pentenoic acid (available fromTokyo Kasei Kogyo Co., Ltd.) and 59.3 mg (4.5×10⁻² mmol) of[RuI(p-cymene){(R)—(SO₃Na)₂BINAP}]I were put in a 200 mL autoclave, andthe atmosphere in the autoclave was replaced with nitrogen. 20 mL ofdegassed distilled water and 22 mL of degassed methylene chloride wereadded to the mixture, and trans-2-methyl-2-pentenoic acid was reacted at80° C. for 6 hours under the same hydrogen pressure as Example 1, toobtain 11.2 g of crude (2R)-methylpentanoic acid. The crude(2R)-methylpentanoic acid was distilled to obtain 10.5 g of purified(2R)-methylpentanoic acid: boiling point 105° C./11 mmHg; GC purity99.1%; optical purity 89.6% ee; optical rotation [α]_(D) ²⁰-17 (c 1.0,MeOH); mass spectrum (20 eV, m/e) 41, 43, 45, 55, 56, 71, 73, 74, 87,101, and 117 (M⁺+1)

Example 4 Synthesis of (2R)-methylhexanoic acid

12.8 g (0.1 mol) of trans-2-methyl-2-hexenoic acid (available from TokyoKasei Kogyo Co., Ltd.) and 66 mg (5×10⁻² mmol) of[RuI(p-cymene){(R)—(SO₃Na)₂BINAP}]I were put in a 200 mL autoclave, andthe atmosphere in the autoclave was replaced with nitrogen. 89.6 mL ofdegassed distilled water and 25.6 mL of degassed methylene chloride wereadded to the mixture, and trans-2-methyl-2-hexenoic acid was reacted at80° C. for 5 hours under the same hydrogen pressure as Example 1, toobtain 12.9 g of crude (2R)-methylhexanoic acid. The crude(2R)-methylhexanoic acid was distilled to obtain 11.8 g of purified(2R)-methylhexanoic acid: boiling point 116° C./11 mmHg; GC purity99.4%; optical purity 89.3% ee; optical rotation [α]_(D) ²⁰-18.7 (c1.05, MeOH); mass spectrum (20 eV, m/e) 41, 43, 55, 56, 57, 69, 73, 74,75, 85, 87, 101, 113, and 131 (M⁺+1).

Example 5 Synthesis of (2R)-ethylhexanoic acid

14.2 g (0.1 mol) of 2-ethyl-2-hexenoic acid (available from Aldrich,trans: 94%, cis: 4.83%) and 53 mg (4.66×10⁻² mmol) of [RuI(p-cymene){(R)—(SO₃Na)₂BINAP}]I were put in a 500 mL autoclave, and the atmospherein the autoclave was replaced with nitrogen. 210 mL of degasseddistilled water and 28.4 mL of degassed methylene chloride were added tothe mixture, and 2-ethyl-2-hexenoic acid was reacted at 80° C. for 8hours under the same hydrogen pressure as Example 1, to obtain 13.9 g ofcrude (2R)-ethylhexanoic acid. The crude (2R)-ethylhexanoic acid wasdistilled to obtain 13.5 g of purified (2R)-ethylhexanoic acid: boilingpoint 125° C./11 mmHg; GC purity 99.1%; optical purity 86.4% ee; opticalrotation [α]_(D) ²⁰-9.1 (c 1.01, MeOH); mass spectrum (20 eV, m/e) 41,43, 45, 55, 57, 73, 87, 88, 101, 115, 116, and 145 (M⁺+1).

Example 6 Syntheses of (2R)-methylbutanoic acid Via Process of RecyclingWater Phase

20 g (0.2 mol) of tiglic acid and 26.3 mg (1×10⁻² mmol) of[RuI(p-cymene){(R)—(SO₃Na)₂BINAP}]I were put in a 200 mL autoclave, andthe atmosphere in the autoclave was replaced with nitrogen. 80 mL ofdegassed distilled water were added to the mixture, and tiglic acid wasreacted at 60° C. for 3 hours under the hydrogen pressure of 1.8 MPa.The temperature of the autoclave was lowered to the room temperature,hydrogen was discharged, and nitrogen was flowed in the autoclave forapproximately 30 minutes to remove the remaining hydrogen. Then, thereaction solution was ejected from a sampling hole of the autoclave intoa 100 mL glass syringe having a needle with the inside diameter of 1.5mm under nitrogen flow utilizing the nitrogen pressure, and left forapproximately 30 minutes. The reaction solution was separated into twolayers, the organic phase of the upper layer and the water phase of thelower layer.

The water phase was isolated and returned into the autoclave, and sealedunder nitrogen to be reused in the next reaction. On the other hand, theoil phase was isolated, dried over anhydrous magnesium sulfate, andconcentrated to recover the solvent, whereby a residue was obtained. Theresidue was distilled to obtain purified (2R)-methylbutanoic acid. Theresults are shown in Table 2.

Then, a solution of 20 g (0.2 mol) of tiglic acid was added into theautoclave containing the water phase used in the above reaction and 0.8mg of [RuI (p-cymene) {(R)—(SO₃Na)₂BINAP}]I while blocking the air. Thetiglic acid was reacted for 3 hours under the same conditions as theabove reaction, and subjected to the aftertreatments in the same manneras above to obtain (2R)-methylbutanoic acid.

The asymmetric hydrogenation of tiglic acid was repeated 10 times suchthat the water phase was isolated under ogen after the reaction andrecycled in the same manner bove. The results of the reactions recyclingthe water phase shown in Table 2. TABLE 2 Recycle Time (h) Conv % eeYield 0 3 100 94.0 87.0 1 3 100 93.8 97.6 2 3 100 93.9 98.5 3 3 99.193.9 98.1 4 6 100 93.5 98.0 5 6 100 93.3 98.3 6 6 100 93.4 98.7 7 6 10093.5 98.6 8 12 100 93.2 98.0 9 12 99.0 93.2 98.5 10 24 100 93.3 98.6

Recycle 1-10 were carried out by adding catalysts of 3% excess amount ofinitial quantity to each recycling.

As the number of recycling times increased, the conversion declined,however, the problem was resolved by extending the reaction time. As forthe conversion, no advantage of using distilled material was identified,though as for the optical purity, its elevation was seen and maintained93% ee, even in cases in which the number of recycling times increased.

Example 7 to 10

The asymmetric hydrogenation was carried out in the same manner asdescribed in Example 1, except that the amount of[RuI(p-cymene){(R)—(SO₃Na)₂BINAP}]I and reaction time were replaced asthose in Table 3, and obtained results as described in Table 3. TABLE 3[Rul(p- cymene){(R)—(SO3Na)2BINAP}]I Example (mg) Time (h) Conv % ee %Yield 7 17.6 7 100 93.1 91.7 8 10.5 7 98.8 93.0 91.1 9 8.79 14 98.8 92.991.8 10 5.27 24 98.6 92.1 94.9

In the methods of the invention, the asymmetric hydrogenation of theα,β-unsaturated carboxylic acid is carried out in water or the two-phasesystem of water and an organic solvent to obtain a desired opticallyactive carboxylic acid with high optical purity, whereby the methods donot require complicated operations of isolating the produced opticallyactive carboxylic acid and the sulfonated BINAP—Ru complex to beexcellent in workability. Further, the methods of the invention canremarkably reduce the costs, can utilize the catalyst efficiently, andare excellent in the workability, because the sulfonated BINAP—Rucomplex used in the asymmetric hydrogenation can be recovered and reusedwithout complicated recovering processes. Furthermore, the recoveredwater phase can be directly reused, and thus, the methods require lesslabor and costs, thereby further improving the workability.

1. A method for producing an optically active carboxylic acidrepresented by the formula [2]:

wherein R¹, R² and R³ independently represent a hydrogen atom, an alkylgroup, an alkenyl group or an aryl group, the groups may have asubstituent, R¹, R² and R³ is not a hydrogen atom simultaneously, R³ isa group other than a hydrogen atom when one of R¹ and R² is a hydrogenatom, R³ is a group other than a hydrogen atom and a methyl group whenboth of R¹ and R² are hydrogen atoms, and R¹ and R² are different groupsother than a hydrogen atom when R³ is a hydrogen atom, and at least oneof the two carbon atoms marked with * represents an asymmetric carbonatom, comprising the step of subjecting an α,β-unsaturated carboxylicacid represented by the formula [1]:

wherein R¹ to R³ have the same meanings as those in the formula [2], inthe presence of a sulfonated BINAP—Ru complex represented by the formula[3]:[RuX(arene) {(SO₃M)₂-BINAP}]X  [3] wherein (SO₃M)₂-BINAP represents atertiary phosphine represented by the formula [4]:

M represents an alkaline metal atom, X represents a chlorine atom, abromine atom or an iodine atom, and arene represents a benzene or analkyl-substituted benzene, in an aqueous solvent, to an asymmetrichydrogenation.
 2. The method according to claim 1, wherein the aqueoussolvent is water or a mixed solvent of water and a water-insolubleorganic solvent.
 3. The method according to claim 1, wherein thesulfonated BINAP—Ru complex is recovered.
 4. The method according toclaim 1, wherein the sulfonated BINAP—Ru complex is recycled.
 5. Amethod for producing an optically active carboxylic acid represented bythe formula [2]:

wherein R¹, R² and R³ independently represent a hydrogen atom, an alkylgroup, an alkenyl group or an aryl group, the groups may have asubstituent, R¹, R² and R³ is not a hydrogen atom simultaneously, R³ isa group other than a hydrogen atom when one of R¹ and R² is a hydrogenatom, R³ is a group other than a hydrogen atom and a methyl group whenboth of R¹ and R² are hydrogen atoms, and R¹ and R² are different groupsother than a hydrogen atom when R³ is a hydrogen atom, and at least oneof the two carbon atoms marked with * represents an asymmetric carbonatom, comprising the step of subjecting an α,β-unsaturated carboxylicacid represented by the formula [1]:

wherein R¹ to R³ have the same meanings as those described above, in thepresence of a recovered sulfonated BINAP—Ru complex used in the methodaccording to claim 1 in water or a mixed solvent of water and awater-insoluble organic solvent to an asymmetric hydrogenation.
 6. Themethod according to claim 5, wherein the α,β-unsaturated carboxylic acidis hydrogenated in the presence of an aqueous solution containing thesulfonated BINAP—Ru complex, and the aqueous solution is obtained byseparating a water phase from the reaction mixture after the asymmetrichydrogenation in the method according to claim 1.